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Preparation method of 16a-hydroxy prednisolone

A technology of hydroxyprednisolone and hydroxyprednisolone acetate is applied in the directions of organic chemistry methods, chemical instruments and methods, steroids, etc., can solve problems such as many impurities and low yields, and achieves simple and convenient production and operation , Reduce the preparation cost, the production process is economical and environmentally friendly

Active Publication Date: 2017-12-19
HUNAN KEREY BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The technical problem to be solved in the present invention is, for the fourth step in the above-mentioned 16a-hydroxyprednisolone synthesis: the problems that there are many impurities and low yield in the hydrolysis reaction of 16a-prednisolone acetate, a new method is provided The hydrolysis method is used to prepare 16a-hydroxyprednisolone, which simplifies the production operation, reduces the impurities produced by side reactions in the production process, greatly improves the overall synthesis yield, and greatly reduces the preparation cost

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0012] A. Preparation of solid-phase base catalyst

[0013] In a 1000ml three-necked flask, add a solution made of 50g of solid alumina, 300ml of tap water, 200ml of tap water and 15g of sodium carbonate, and stir the adsorption reaction at 25-30°C for 3-4 hours. After the reaction, evaporate the water under reduced pressure It was nearly dry, taken out and dried to obtain 50.1 g of solid-phase base catalyst with a water content of 5.6% and a weight yield of 102%.

[0014] B. Synthesis of 16a-hydroxyprednisolone

[0015] In a 2000ml three-necked flask, add 100g of the raw material 16a-prednisolone hydroxyacetate, 1500ml of toluene, and dissolve it completely under stirring, then add 30g of the above-mentioned solid-phase alkali catalyst, keep warm at 40-45°C and stir for hydrolysis reaction 6-8 Hours, TLC confirmed the reaction end point, after the reaction, while hot nitrogen pressure filtration, the filter cake was soaked and washed twice with 500ml toluene, and then the so...

Embodiment 2

[0017] A. Preparation of solid-phase base catalyst

[0018] According to the method described in A in the above-mentioned Example 1, only the alumina is replaced by silica gel, and 49.8 g of solid-phase alkali catalysts with silica gel as a carrier are obtained, and the water content is 6.8%.

[0019] B. Synthesis of 16a-hydroxyprednisolone

[0020] In a 2000ml three-neck flask, add 100g of raw material 16a-prednisolone hydroxyacetate, 1500ml of alcohol, stir to dissolve completely, then add 30g of solid-phase alkali catalyst, keep warm at 40-45°C and stir for 6-8 hours of hydrolysis reaction , TLC confirms the end point of the reaction, after the reaction is completed, filter under hot nitrogen pressure, soak and wash the filter cake twice with 500ml alcohol, then recover the solid-phase alkali catalyst and apply it mechanically; Lower the temperature, add tap water for water analysis, centrifuge, and decompress the filtrate to recover residual alcohol, then discharge it int...

Embodiment 3

[0022] A. Preparation of solid-phase base catalyst

[0023] According to the method described in A in above-mentioned embodiment one, just change aluminum oxide into calcium carbonate, sodium carbonate into sodium hydroxide, make the solid-phase base catalyst 49.6g with calcium carbonate as carrier, water content 4.8%.

[0024] B. Synthesis of 16a-hydroxyprednisolone

[0025] In a 2000ml three-necked bottle, add 100g of raw material 16a-prednisolone hydroxyacetate, 1500ml of chloroform, and dissolve it completely under stirring, then add 30g of the basic calcium carbonate solid-phase alkali catalyst prepared by the above-mentioned A, and keep it warm at 40 ~ Stir the hydrolysis reaction at 45°C for 6-8 hours, and confirm the end point of the reaction by TLC. After the reaction, press filter while hot nitrogen, soak the filter cake twice with 500ml chloroform, and then recover the solid-phase alkali catalyst and apply it mechanically; the filtrate and the washing liquid are com...

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PUM

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Abstract

The invention discloses a preparation method of 16a-hydroxy prednisolone. The preparation method comprises the following steps: dissolving 16a-hydroxy prednisolone acetate into an organic solvent, adding an inert solid carrier adsorbed with strong base as a hydrolysis reaction solid-phase base catalyst, and hydrolyzing 21-acetate to obtain a 16a-hydroxy prednisolone crude product; and carrying out lower alcohol recrystallization on the crude product under the condition of below C4 to obtain a 16a-hydroxy prednisolone competitive product, wherein the refined weight yield is 85% to 90%, and the preparation weight total yield is 75% to 80%. The solid carrier is selected from aluminum oxide, silica gel or calcium carbonate; the base catalyst is selected from sodium carbonate; and the organic solvent is selected from methylbenzene or chloroform. Compared with a traditional method, the method disclosed by the invention is simple and convenient in production operation, impurities generated in traditional production can be greatly reduced, and the total yield for synthesis is greatly improved; compared with the traditional method, the production cost is reduced by 10% to 15%; and a synthetic reaction solvent can be recycled, and industrial production is facilitated.

Description

technical field [0001] The invention relates to a preparation technology of a steroid hormone drug intermediate, specifically a production method for synthesizing 16a-hydroxyprednisolone by using 16a-hydroxyprednisolone acetate as a raw material and adopting solid-phase alkali-catalyzed hydrolysis. Background technique [0002] 16a-Hydroxyprednisolone (molecular formula C21H28O6), chemical name 11b, 16a, 17a, 21-tetrahydroxy-pregna-1,4-diene-3,,20-dione, is a The key intermediate of steroidal adrenocorticotropic hormone drugs, using it as a raw material, one-step condensation reaction with acetone to produce desonide, and one-step condensation reaction with n-butyraldehyde to prepare budesonide, neide steroidal adrenocorticotropic hormone Drugs are a class of potent local anti-inflammatory agents, such as budesonide, which is mainly used clinically for the treatment of various diseases such as various rhinitis, acute and chronic bronchitis, etc., with low side effects, good ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J5/00B01J27/232
CPCY02P20/584C07J5/0092B01J27/232C07B2200/07
Inventor 甘红星胡爱国吴来喜谢来宾
Owner HUNAN KEREY BIOTECH
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